Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification

Micucci, C.; Orciari, Silvia; Catalano, Alfonso

doi:10.1371/journal.pone.0105550

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…Another study has reported the translocation of GLUT1 and GLUT4 on the cell surface by insulin treatmen via a different pathway of signal transduction in mouse NIH3T3-L1 adipocytes [ 38 ]. In addition, a previous study has reported that the chronic hyperglycemia also upregulated GLUT1 expression and promoted the K-Ras-induced lung tumorigenesis in mice [ 39 ]. In the present study, the Western blot analysis did not demonstrate positive GLUT4 expression in KD cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions

Tanaka¹,

Kitajima²,

Miyake³

et al. 2015

PLoS ONE

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Gastric cancer grows under a hypoxic environment. HIF-1α is known to play an important role in controlling the production of reactive oxygen species (ROS) in the mitochondria under hypoxic conditions. We previously established HIF-1α knockdown (KD) cells and control (SC) cells in the 58As9 gastric cancer cell line. In this study, we revealed that KD cells, but not SC cells, induced apoptosis under conditions of hypoxia (1% O2) due to excessive production of ROS. A quantitative RT-PCR analysis demonstrated that the expressions of ten genes, which are involved in the control mechanisms of ROS (including the Warburg effect, mitophagy, electron transport chain [ETC] modification and ROS scavenging), were regulated by HIF-1α. Moreover, the promotion of glucose uptake by glucose plus insulin (GI) treatment enhanced the apoptotic effect, which was accompanied by further ROS production in hypoxic KD cells. A Western blot analysis showed that the membranous expression of GLUT1 in KD cells was elevated by glucose and/or insulin treatments, indicating that the GI-induced glucose uptake is mediated by the increased translocation of GLUT1 on the cell membrane. Finally, the anti-tumor effect of HIF-1α knockdown (KD) plus GI was evaluated using a tumor xenograft model, where a hypoxic environment naturally exists. As a result, the GI treatment strongly inhibited the growth of the KD tumors whereby cell apoptosis was highly induced in comparison to the control treatment. In contrast, the growth of the SC tumors expressing HIF-1α was not affected by the GI treatment. Taken together, the results suggest that HIF-1α inhibition plus GI may be an ideal therapy, because the apoptosis due to the destruction of ROS homeostasis is specifically induced in gastric cancer that grows under a hypoxic environment, but not in the normal tissue under the aerobic conditions.

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Section: Discussionmentioning

confidence: 99%

The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions

Tanaka¹,

Kitajima²,

Miyake³

et al. 2015

PLoS ONE

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“…In NSCLC, there is a positive correlation between GLUT1 expression and the EGFR and KRAS oncogenes; GLUT1 overexpression is also correlated with an aggressive phenotype [127]. In an in vivo study by Micucci et al, the hyperglycemic state induced by streptozotocin accelerated lung cancer progression [128]. Hyperglycemia induces reactive oxygen species (ROS) production by increasing oxidative stress, decreases mitochondrial function and tilts the metabolic processes to glycolysis [120,129].…”

Section: Metabolic Adaptations Induced By Hypoxia In Cancermentioning

confidence: 99%

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Tirpe

Gulei

Ciortea

et al. 2019

IJMS

275

183

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Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-β, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect—a metabolic switch to glycolysis—and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.

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“…Moreover, our current study provides compelling evidence that hyperglycemia, after activation of oncogenic K-Ras, exerts its pro-tumorigenic effects by maintaining a sub-population of cancer tumor-initiating cells, namely lung bronchio-alveolar stem cells (BASCs) [56]. …”

Section: Mechanisms That Increase the Risk Of Cancer In Metabolic Synmentioning

confidence: 99%

Current perspectives between metabolic syndrome and cancer

et al. 2016

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Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome – related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care.

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Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification

Cited by 17 publications

References 30 publications

The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions

The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Current perspectives between metabolic syndrome and cancer

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